The overall goal of our research is to elucidate underlying mechanisms, pathways and biological markers which may predispose individuals to advanced age-related macular degeneration (AMD) so that appropriate preventive and therapeutic targets can be developed. Commonly, the degeneration of the retina has already begun by the time the patient is diagnosed with AMD in the clinic. Most current treatments are directed against neovascular AMD (an advanced and more severe form of the disease), require invasive delivery methods, are limited in their applicability, and not capable of preventing or reversing vision loss over the long term. Significant work in AMD genetics has established alleles as well as haplotypes on chromosomes 1 and 10, particularly in CFH and LOC387715/ARMS2/HTRA1, as having large influences on AMD risk in populations of various ethnicities. As a result of the CFH findings, further investigation of the complement pathway has revealed associations between AMD risk and rare alleles in the C2/CFB, C3 and CFH1-5. Although these studies illustrate the importance of studying entire genetic pathways rather than one gene in isolation to develop effective therapies for common diseases such as AMD, there are many AMD free individuals in the population that harbor these disease susceptibility genotypes/haplotypes and a substantial number of AMD patients who lack risk variants in these loci. While these findings have begun to provide insights into AMD etiology, there are still many questions about AMD risk and pathogenesis that cannot be explained by the known AMD-related genes and therefore important loci remain to be identified and characterized. In this competitive renewal proposal, the applicants, working with leading investigators from diverse disciplines (molecular genetics, statistical genetics and proteomics), aim to further identify and evaluate the role of genetic variants using a phenotypically well-characterized and documented cohort of extreme sibpairs. The approach is multi-pronged and will employ state of the art methodologies to pinpoint biologically relevant disease targets and their modifiers that may predispose an individual to neovascular AMD. To this end, the applicants will initially evaluate data from high density SNP/CNV arrays that are directly relevant to specific candidate regions and genes obtained from preliminary findings of genomic convergence between linkage, genome wide association and gene expression analysis on risk of neovascular AMD. The applicants anticipate that results of this project will provide a solid foundation on which to build a better understanding of AMD pathogenesis and thereby furthering the development of strategies for therapy and prevention of this disease.